Attacking MALT1 for ABC-DLBCL therapy

Diffuse large B-cell lymphoma (DLBCL) comprises the largest group of non-Hodgkin lymphoma (NHL). DLBCL can be classified according to their cellular origin and patients with the activated B-cell (ABC) subtype have an inferior prognosis relative to those with the germinal center B-cell (GCB) subtype. Constitutive anti-apoptotic NF-κB signaling is a hallmark of ABC-DLBCL. NF-κB activation is caused by chronic active B-cell receptor (BCR) signaling or constitutive MYD88 signaling. Oncogenic mutations that contribute to pathogenesis of ABC-DLBCL tumors have been identified in critical components of both pathways (Figure 1) [1]. Target directed approaches for ABC-DLBCL therapy have largely focused on the inhibition of upstream protein kinase [2]. Chronic BCR signaling engages the adaptors CD79A and CD79B in a Syk-dependent mechanism. Syk is constitutively active in many B-cell lymphomas and a clinical phase I/II trial using the Syk inhibitor fostamatinib disodium (FosD, AstraZeneca) shows some response also in DLBCL patients. However, most oncogenic mutations in ABC-DLBCL occur further downstream revealing that Syk may not be an optimal target. Downstream of CD79A/B, Btk and PKCβ bridge proximal BCR signaling events to the CARMA1 (CARD11)-BCL10-MALT1 (CBM) complex. Over 20% of ABC-DLBCL tumors carry oncogenic mutations in CD79A/B. Indeed, the irreversible Btk inhibitor ibrutinib (PCI-32765, Pharamcyclics) and the panPKC inhibitor sotrastaurin (STN) are inhibiting the outgrowth of CD79 mutant ABC-DLBCL in preclinical models [3, 4]. Furthermore, positive clinical responses in a phase II trial were reported in relapsed/refractory DLBCL with the selective PKCβ inhibitor enzastarin (LY317615, Eli Lilly) [5]. However, none of these potential drugs is able to target ABC-DLBCL tumors with lesions downstream of PKCβ or in parallel pathways, such as CARMA1 of MYD88, respectively. Downstream of PKCβ the CBM subunit MALT1 has attracted great attention as a potential therapeutic target [6]. MALT1 serves a dual role in NF-κB signaling in response to antigen receptor stimulation. MALT1 is an adaptor that recruits and activates the IκB kinase (IKK) complex, the gatekeeper of canonical NF-κB. In addition, MALT1 is a paracaspase with a caspase-like proteolytic activity that is required for full NF-κB signaling and survival of ABC-DLBCL cells. MALT1 cleaves and thereby inactivates negative regulators of canonical NF-κB, such as the tumor suppressor A20 and the NF-κB subunit RelB which both counteract pro-survival functions of canonical IKK/NF-κB signaling. Two classes of MALT1 inhibitors have now been identified that effectively and selectively inhibit the growth of ABC-but not GCB-DLBCL in vitro and in vivo [7, 8]. …